Recent investigation into the molecular mechanisms of malignant transformation and behavior promises to yield real improvements in the management of oral cancer. A spectrum of genetic alterations in squamous cell carcinoma (SCC) of the upper aerodigestive tract has been described targeting the p53, p16, PTEN, Cyclin D1 and RB genes. Specific areas of chromosomal loss have been mapped as well, for which the target genes are unknown. Efforts to apply this knowledge in a variety of clinical settings have already begun. Translational research uncovers phenotypic correlates of genetic changes in order to better understand their mechanism of action. Genetic alterations may also serve as biomarkers for detection of cancer cells and for prognostication. Early detection of cancer and accurate prediction of the response of individual tumors to specific therapeutic options would be invaluable for the management of disease. This proposal seeks to expand previous translational research in three ways. First, it will investigate the utility of genetic markers to augment routine histologic evaluation. Mutations of p53 will be used to map the extent of disease in surgical resection margins and the results correlated with local recurrence and survival. Second, the spectrum of genetic alterations in well defined groups of patients will be catalogued and correlations sought with clinical outcome and epidemiological factors. This work will attempt to identify useful prognostic markers that can direct therapeutic decisions, as well as to focus future research efforts on markers of particular phenotypic significance. The third aim is to validate a new molecular strategy for early detection of oral SCC. A panel of microsatellite markers with a high propensity for shifts in oral cancer will be tested in order to demonstrate its specificity for cancer and sensitivity for detection of minimal disease. DNA from exfoliated cells from the oral cavities of cancer patients and controls will be examined for tumor-specific shifts not present in germline DNA from peripheral blood lymphocytes. This approach will also be applied for surveillance of patients after curative therapy is complete. Through these three translational strategies, it is likely that valuable benefits will accrue both for understanding the basic behavior of oral SCC, and for the management of patients with this devastating disease.